A Novel Humanized Mouse Model for Studying HIV/HCV Co-Infection and Liver Disease Alcohol consumption by HIV+ individuals has been associated with increased susceptibility to viral co- infection and liver disease. HIV-1 and HCV (hepatitis C virus) coinfection, highly prevalent as a result of shared transmission routes, has been correlated with accelerated liver disease progression in HCV infected patients. A mouse model that allows HCV and/or HIV replication and pathogenesis is urgently needed to study the effect of ethanol and HIV coinfection on HCV infection and liver pathogenesis. The Rag2-C double knockout (DKO) mouse lacks T/B and NK cells, and allows development of a functional human immune system with human Hematopoietic Stem Cell (DKO-hu HSC mice). Normal human T, B, and dendritic cells are present in lymphoid tissues such as thymus, spleen, peripheral blood (PB) and lymph nodes (LN),as well as liver. We also show that DKO-hu-HSC mice allow high and persistent levels of HIV-1 infection in lymphoid organs and liver. Human CD4+ T cells are gradually depleted by HIV-1 in a dose-dependent manner, correlated with induction of inflammatory cytokines and lymphocyte infiltration in the liver. In addition, HIV-1 infection persisted in infected DKO-hu HSC mice for >20 weeks, with HIV-1 in lymphoid and liver tissues. Furthermore, HIV-1 or EBV infection induces human immune responses. Recently, we co-engrafted human hepatocytes and human immune system in the DKO mouse transplanted with human hepatocyte progenitor cells and CD34+ HSC cells (DKO-hu HSC/Hep mice). I propose to optimize the DKO-hu HSC/Hep mouse to increase human hepatocyte engraftment by selectively depleting murine hepatocytes and promoting human hepatocytes in the DKO-hu HSC/Hep mouse. We will also study how ethanol and HIV-1 coinfection affect HCV infection and liver pathogenesis in this model. The long-term goals of this project are to 1) develop a relevant mouse model to investigate the immuno- pathogenesis of HCV infection and HCV/HIV coinfection, 2) study how alcohol affects HIV or HCV infection and liver pathogenesis in vivo. Specifically, we will optimize the DKO-hu HSC/Hep model for studying HCV infection and immuno-pathogenesis. We will establish the effect of alcohol treatment on the infection and liver pathogenesis of HCV. We will also investigate how HIV co-infection affects HCV replication and pathogenesis. These studies will establish the foundation for future study and shed light on novel therapeutic strategies for controlling liver diseases associated with HIV and/or HCV infection. PUBLIC HEALTH RELEVANCE: The long-term goals of this project are to 1) develop a novel mouse model to investigate the immuno- pathogenesis of HCV infection and HCV/HIV coinfection, and 2) study how alcohol affects HIV or HCV infection and liver pathogenesis in vivo. We will establish the effect of alcohol treatment on the infection and liver pathogenesis of HCV. We will also investigate how HIV co-infection affects HCV replication and pathogenesis. These studies will establish the foundation for future study and shed light on novel therapeutic strategies for controlling liver diseases associated with HIV and/or HCV infection.